The goal of this proposal is to validate a primate xenograft model in immunodeficient mice for studies of the mechanisms underlying menstrual bleeding. Because only women and nonhuman primates menstruate, nonhuman primates are the best animal models for studies of menstrual mechanisms. With a xenograft approach, the endometrium from one donor can be grafted into multiple immunodeficient mice. The tissue from each macaques is therefore amplified and made available for different experimental protocols permitting more extensive studies than in the intact animal. These studies could include basic studies of the mechanisms underlying endometrial bleeding and screening of drugs that inhibit endometrial bleeding, including, antiprogestins, and mesoprogrestins. In preliminary studies we showed that macaque endometrium can be grafted into immunodeficient SCID TM mice. However, several questions remain to be answered. First, which immunodeficient mouse strain is the best host for monkey endometrial grafts? Second, what is the best anatomical site for endometrial xenografting in the mice? Third, will primate endometrial xenografts display normal endometrial histology, express steroid receptors, show hormonal responsiveness, and undergo normal menstruation in mice? Finally, can the effects of specific drugs on endometrial vascular development and bleeding patterns be studied in such a model? To answer these questions we propose the following specific aims: 1. Compare alymphoid common gamma (Yc) null/RAG-2 null mice with RAG-2 null mice as hosts for rhesus macaque endometrial xenografts, and determine the best graft site in these mice. 2. Ascertain the most appropriate hormonal regimen to produce normal endometrial histoarchitecture, hormonal responsiveness and menstruation in the xenografts. 3. Compare the effects of an antiprogestin with a recently developed mesoprogestin on endometrial development and bleeding patterns in endometrial xenografts. Our hypothesis is that in the most appropriate strain of mice, treated with the most appropriate hormonal regimen, monkey endometrial grafts will undergo typical 28 day menstrual cycles marked by typical menstrual bleeding. A successful xenograft model will provide a new tool for analyzing the mechanisms underlying menstrual bleeding.